Arylalkyl amines useful for lowering intraocular pressure

ABSTRACT

Intraocular hypertensive diseases such as glaucoma are treated with compounds represented by formula I ##STR1## or a pharmaceutically acceptable acid addition salt thereof, wherein R 1  is alkyl of two to four carbon atoms; 
     R 2  is --(CH 2 ) n  --C 6  H 4  --R 5  ; where 
     n is an integer from 1 to 4; and 
     R 5  is --H, --OH, halo, lower alkyl, lower alkoxy, ureido, lower alkyl-ureido, lower alkyl-amido, or formamido; 
     R 3  is hydro or hydroxy; and 
     R 4  is hydro, lower alkyl, amino, or lower alkylamino.

This is a division of pending application Ser. No. 722,046, filed Apr.16, 1985, now U.S. Pat. No. 4,642,378 incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to arylalkyl aminoethylaniline derivatives andthe pharmaceutically acceptable acid addition salts thereof. Thesecompounds are administered to the eye to lower intraocular pressure. Theinvention also relates to a pharmaceutically acceptable compositioncontaining an effective amount of at least one of the compounds incombination with a suitable excipient, the composition being useful forthe treatment of intraocular hypertensive diseases such as glaucoma inmammals.

2. Related Disclosures

Certain alkyl and dialkyl aminoethylanilines are known. See, forexample, U.S. Pat. Nos. 4,287,211, 4,404,222, 3,803,230, and 3,689,524and German Pat. No. 2,612,354. A novel class of arylalkylaminoethylaniline derivatives has now been prepared.

SUMMARY OF THE INVENTION

The first aspect of this invention is a compound of formula I useful inthe treatment of intraocular hypertension. ##STR2## or apharmaceutically acceptable acid addition salt thereof, wherein R₁ isalkyl of two to four carbon atoms;

R₂ is --(CH₂)_(n) --C₆ H₄ --R₅ ; where

n is an integer from 1 to 4; and

R₅ is --H, --OH, halo, lower alkyl, lower alkoxy, ureido, loweralkyl-ureido, lower alkyl-amido, or formamido;

R₃ is hydro or hydroxy; and

R₄ is hydro, lower alkyl, amino, or lower alkylamino.

Another aspect of the invention is the method of treatment ofintraocular hypertensive diseases such as glaucoma with a compound offormula I.

Another aspect of the invention is a composition useful in the treatmentof intraocular hypertensive diseases such as glaucoma in mammals whichcomposition comprises an effective amount of at least one compoundchosen from those represented by formula I above or a pharmaceuticallyacceptable acid addition salt thereof and a pharmaceutically suitableexcipient.

Another aspect of the invention is the use of a compound of formula I,or a pharmaceutically acceptable acid addition salt thereof, to preparea composition useful in the treatment of intraocular hypertensivediseases such as glaucoma in mammals.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

The broadest aspect of the present invention is the compound of formulaI, or a pharmaceutically acceptable acid addition salt thereof: ##STR3##wherein R₁ is alkyl of two to four carbon atoms; and

R₂ is --(CH₂)_(n) --C₆ H₄ --R₅ ; where

n is an integer from 1 to 4; and

R₅ is --H, --OH, halo, lower alkyl, lower alkoxy, ureido, loweralkyl-ureido, lower alkyl-amido, or formamido;

R₃ is hydro or hydroxy; and

R₄ is hydro, lower alkyl, amino, or lower alkylamino.

One preferred subgenus of compounds of formula I is that wherein R₃ ishydro, particularly where n is 2. A preferred class of the invention isthat wherein R₄ is amino. A preferred compound is that wherein R₂ isphenethyl and R₁ is n-propyl. Another preferred compound is that whereinR₅ is 3-ureido and R₁ is n-propyl. Another preferred compound is thatwherein R₅ is hydroxy and R₁ is n-butyl. Another preferred class of theinvention is the class wherein n is 4. A preferred subclass of theinvention is that wherein R₄ is methyl. A preferred compound is thatwherein R₅ is hydro and R₁ is n-propyl.

Another preferred subgenus of compounds of formula I is that wherein R₃is hydroxy, particularly where R₄ is amino. A preferred compound is thatwherein R₂ is phenethyl and R₁ is n-propyl. Another preferred compoundis that wherein R₅ is 3-hydroxy and R₁ is n-propyl.

Another aspect of the invention is the method of treating a mammal withelevated intraocular pressure by administering directly to the eye ofsaid mammal a compound of formula I.

One preferred subgenus of compounds of formula I is that wherein R₃ ishydro, particularly where R₄ is amino. A preferred compound is thatwherein R₂ is phenethyl and R₁ is n-propyl. Another preferred compoundis that wherein R₂ is 3-ureidophenethyl and R₁ is n-propyl.

Another aspect of the invention is a pharmaceutical composition fortreating intraocular hypertension comprising a pharmaceuticallyacceptable, non-toxic carrier and a therapeutically effective amount ofa compound of formula I.

Another aspect of the invention is the use of a compound of formula I,or a pharmaceutically acceptable acid addition salt thereof, to preparea composition useful in the treatment of intraocular hypertensivediseases such as glaucoma in mammals.

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term "lower alkyl" refers to a straight or branched chain monovalentsubstituent consisting solely of carbon and hydrogen, containing nounsaturation and having from one to four carbon atoms. Examples of loweralkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl and t-butyl.

The term "--C₆ H₄ --" refers to a disubstituted phenyl group.

The term "ureido" refers to --NHCONH₂.

The term "formamido" refers to --NHCHO.

The term "lower alkyl-amido" refers to --NHCOR, where R is lower alkylas defined above.

The term "halo" refers to chloro, bromo, or iodo.

The term "pharmaceutically acceptable acid addition salts" refers tosalts of the subject compounds which possess the desired pharmacologicalactivity and which are neither biologically nor otherwise undesirable.These salts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; ororganic acids such as acetic acid, propionic acid, glycolic acid,pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid and the like.

The term "direct administration" means administration directly to theeye of the subject, and excludes general systemic administration. Directadministration includes, without limitation, topical application ofaqueous solutions and ointments, administration of controlled releasedevices, and subconjunctival injection.

The term "treatment" as used herein covers any treatment of anintraocular hypertensive disease in a mammal, particularly a human, andincludes:

(i) preventing the disease from occurring in a subject which may bepredisposed to the disease but has not yet been diagnosed as having it;

(ii) inhibiting the disease, i.e., arresting its development; or

(iii) relieving the disease, i.e., causing regression of the disease.

ADMINISTRATION AND FORMULATION

Ophthalmic preparations are sterile products for either topicalapplication to the eyes or instillation into the space (cul-de-sac)between the eyeball and the eyelids. Presently available opthalmicpreparations incluse solutions, suspensions, ointments, and controlledrelease devices. Presently available topical treatment of eye diseasesinclude topically applied ophthalmic drops, solutions, suspensions orointment or their subconjunctival injection.

The composition of this invention comprises a compound of this inventionor a salt thereof in admixture with an ophthalmologically acceptableexcipient.

An excipient is opthalmologically acceptable if it is non-irritating andnon-toxic.

The ophthalmic composition may be aqueous or non-aqueous, and it may bein the form of a solution, suspension, gel, ointment, slow releasepolymer, or other. The amount of active ingredient will vary with theparticular formulation and disease state but generally will between0.001-10% wt/vol of active ingredient per individual application dose.

Pharmaceutical ophthalmic compositions are typically provided assterilized aqueous solutions (i.e. eyedrops) containing 0.001% to 10%wt/vol.; most preferably 0.005% to 1% of the active ingredient, alongwith a suitable buffer, stabilizer, and preservative. The totalconcentration of solutes should be such that, if possible, the resultingsolution is isotonic with the lacrimal fluid (though this is notabsolutely necessary) and has an equivalent pH (in the range of pH 6-8).Typical preservatives/sterilants are phenylmercuric acetate, thimerosal,chlorobutanol, and benzalkonium chloride. Typical buffer systems andsalts are based on, for example, citrate, borate or phosphate; suitablestabilizers include glycerin and polysorbate 80. The aqueous solutionsare formulated simply by dissolving the solutes in a suitable quantityof water, adjusting the pH to about 6.8-8.0, making a final volumeadjustment with additional water, and sterilizing the preparation usingmethods known to those skilled in the art.

The dosage level of the resulting composition will, of course, depend onthe concentration of the drops, the condition of the subject and theindividual magnitude of responses to treatment. However, typical dosageranges might be about 2-10 drops of 0.1% solution of active ingredientonce to three times per day.

Most ophthalmic solutions and suspensions contain an aqueous rather thanan oily vehicle. Ophthalmic ointments usually contain a whitepetrolatum-mineral oil base, often including anhydrous lanolin, whilesome have a polyethylene-gelled mineral oil base.

Solutions are the most commonly used type of preparation for the localmedication of eyes. They are easily instilled and rarely cause adversereactions. The vehicle should not interfere with vision and should notinterfere with regeneration of the corneal epithelium.

Suspensions have the advantage of more extended action and thedisadvantage that it is difficult to avoid the presence of a fewparticles which are large enough to cause irritation.

Eye ointments are sterile preparations for application to theconjunctival sac or lid margin. They have advantages of more prolongedcontact and effect, minimal irritation on initial installation, slowermovement into lacrimal ducts, greater storage stability, and lesslikelihood of contamination problems. Their disadvantages are that theyproduce a film over the eye thereby blurring vision, and they mayinterfere with the firm attachment of new corneal epithelial cells totheir normal base. Ointments affect the outside and edges of theeyelids, the conjunctiva, the cornea, and the iris, depending on theirability to penetrate the outer covering of the eyeball.

Ophthalmic ointments comprising active ingredients can be used on theoutside and edges of the eyelids, the conjunctiva, the cornea, and theiris. Most ophthalmic ointments are prepared with a base of white oryellow petrolatum and mineral oil, often with added anhydrous lanolin orpolyethylene-gelled mineral oil. Whichever base is selected, it must benonirritating to the eye, permit diffusion of the drug throughout thesecretions bathing the eye, and retain the activity of the medicamentfor a reasonable period of time under proper storage conditions.

Compounds of this invention may also be administered by othernonsystemic modes. Ophthalmic packs may be used to give prolongedcontact of the solution with the eye. For example, a cotton pledgetsaturated with an ophthalmologically suitable solution of a compound ofthis invention may be inserted into the superior or inferior fornix.Medicated controlled release ophthalmic disks may produce effects bothmore intense and prolonged than solutions. See, e.g., U.S. Pat. No.4,190,642, incorporated herein by reference, which discloses acontrolled-release device for administering compounds to the eye, whichmay be useful in the practice of this invention.

The compounds of the invention may also be administered by the way ofiontophoresis. This procedure keeps the solution in contact with thecornea in an eyecup bearing an electrode. Diffusion of the activecompound is effected by difference of electrical potential. Remington'sPharmaceutical Sciences, 15th Ed., 1489-1504, (1975).

PREPARATION OF THE INVENTION

Compounds of formula I are prepared by the reaction sequence shownbelow. ##STR4## wherein R₁, R₂, R₃, and R₄ are as defined above in thebroadest aspect of the invention, Ts is tosyl (p-toluenesulfonyl), A isbenzyloxy (BzO) or hydro, BzCl is benzyl chloride, and R is lower alkyl.

When compounds in which R₃ is hydro and R₅ is not hydroxy are desired,steps (1) and (7) are not necessary and are omitted; in such cases step(6a, b, c, or d) is the final step.

For compounds in which R₃ is hydroxy, 4-hydroxy-3-nitrophenylacetic acid(II), available, e.g., from Aldrich Chemical Co., is first converted tothe methyl ester, then reacted with an equimolar amount of benzylchloride, also available, e.g., from Aldrich Chemical Co., using theWilliamson Ether Synthesis to yield a hydroxy-protected methyl4-benzyloxy-3-nitrophenylacetate (III, A=BzO). The reaction is usuallyperformed using potassium carbonate in refluxing acetonitrile orethanol. (Step 1.)

The protected nitrophenylacetic acid ester (III, A=BzO) is then reduced,using borane-methyl sulfide in a tetrahydrofuran (THF) solution at roomtemperature. After acidification with HCl in methanol, the solution isevaporated, and the product 4-benzyloxy-3-nitrophenylethanol (IV, A=BzO)extracted from aqueous sodium carbonate with diethyl ether (Et₂ O).Similarly, compounds in which A=H may be prepared by the same method,substituting 3-nitrophenylacetic acid (III, A=H) for methyl4-benzyloxy-3-nitrophenylacetate. 3-Nitrophenylacetic acid is availablecommercially from e.g. Aldrich Chemical Co. (Step 2.)

The 4-benzyloxy-3-nitrophenylethanol (IV, A=BzO) is then reacted with amolar excess of p-tolunesulfonyl chloride in pyridine at 0° C. toproduce a 4-benzyloxy-3-nitrophenylethyl tosylate (V, A=BzO). Thetosylate (V, A=BzO) is extracted using ethyl acetate Similarly,compounds in which A=H may be prepared by the same method, substituting3-nitrophenylethanol (IV, A=H) for 4-benzyloxy-3-nitrophenylethanol.(Step 3.)

The desired arylalkyl-alkyl amine is then prepared by reaction of asuitable arylalkanol with p-toluenesulfonyl chloride to form thetosylate, followed by reaction with a suitable alkyl amine indimethylformamide (DMF) at 65° C.

The tosylate (V, A=BzO) is reacted with an equimolar amount of thedesired arylalkyl-alkyl amine in DMF at 65° C. to produce a2-benzyloxy-5-(N-alkyl-N-arylalkyl) aminoethylnitrobenzene (VI, A=BzO).Similarly, compounds in which A=H may be prepared by the same method,substituting 3-nitrophenylethyl tosylate (V, A=H) for4-benzyloxy-3-nitrophenylethyl tosylate. (Step 4.)

The 2-benzyloxy-5-(N-alkyl-N-arylalkyl)aminoethylnitrobenzene (VI,A=BzO) is then reduced to a2-benzyloxy-5-(N-alkyl-N-arylalkyl)aminoethylaniline derivative (VII,A=BzO) with hydrazine and Raney nickel in refluxing ethanol at ambientpressure with an equimolar amount of hydrogen, using the general methodknown for other unrelated compounds. See, e.g., Introduction to OrganicChemistry, by Andrew Streitwieser, Jr., and Clayton H. Heathcock, Ch.32, p. 961 (1976). Similarly, compounds in which A=H may be prepared bythe same method, substituting3-(N-alkyl-N-arylalkyl)aminoethylnitrobenzene (VI, A=H) for2-benzyloxy-5-(N-alkyl-N-arylalkyl)aminoethylnitrobenzene. (Step 5.)

The sequence is completed by reacting the aniline derivative with anequimolar amount of the appropriate reactive formyl derivative,carboxylic acid derivative, isocyanate, or alkylisocyanate.

If a formamido derivative (VIIIa, A=H or BzO) is desired, the novelaniline derivative (VII, A=H or BzO) is reacted at 0° C. with anequimolar amount of an appropriate reactive formyl derivative (e.g.,formic acetic anhydride, which may be generated in situ from sodiumformate and acetyl chloride, which are commercially available) in anappropriate aprotic base. (Step 6a.)

To produce a compound in which R₄ is lower alkyl (VIIIb, A=H or BzO),the aniline derivative (VII, A=H or BzO) is reacted at 25° C. with anequimolar amount of an appropriate reactive carboxylic acid derivative,especially an acyl halide, in an appropriate aprotic base. Carboxylicacid chlorides are available commercially, or may be prepared fromcommercially available carboxylic acids by methods known in the art.(Step 6b.)

To produce a ureidobenzene derivative (VIIIc, A=H or BzO), the anilinederivative (VII, A=H or BzO) is reacted at 25° C. with an equimolaramount of an appropriate cyanate salt, e.g., potassium cyanate, in anacidic medium. (Step 6c.)

To produce an alkyl ureidobenzene derivative (VIIId, A=H or BzO), theaniline derivative (VII, A=H or BzO) is reacted at 25° C. with anequimolar amount of an appropriate alkyl isocyanate, using the generalmethod known in the art for unrelated compounds. See, e.g., Introductionto Organic Chemistry, Streitwieser & Heathcock, Ch. 27, p. 801. Alkylisocyanates may be obtained commercially, or may be produced by reactingthe appropriate alkyl halide with a reactive cyanate salt. (Step 6d.)

In compounds wherein neither R₃ nor R₅ is hydroxy, Step 6a, b, c, or dproduces the compound of formula I directly. Where R₃ or R₅ is hydroxy,it is necessary to remove the benzyloxy protecting group. This may beaccomplished by the method described in Catalytic Hydrogenation inOrganic Synthesis: Procedures and Commentary, M. Freifelder, (Wiley,1978), p. 109, e.g., by catalytic hydrogenolysis of the penultimatecompound (VIIIa-d) using palladium on carbon in methanol at ambienttemperature and a pressure of 2 atmospheres, affording the compound ofthe invention (I).

In summary, compounds of formula I are prepared by the followingmethods:

Compounds of formula I in which neither R₃ nor R₅ is hydroxy areprepared by reacting a compound of formula VII (where A=H) with anappropriate reactive formyl derivative, carboxylic acid derivative,isocyanate salt, or alkylisocyanate, to produce the correspondingformanilide derivative, alkanylanilide derivative, ureidobenzenederivative, or alkylurea derivative. These reactions may be performed atatmospheric pressure, and at temperatures between the freezing andboiling points of the solvents employed, preferably between about -5° C.and about 110° C., and most preferably at about 25° C.

Compounds of formula I in which R₃ or R₅ is OH are prepared byperforming the same procedure using a compound of formula VII (whereA=BzO), followed by removal of the protecting benzyloxy group, e.g., bycatalytic hydrogenolysis with H₂ over palladium on carbon at about 60°C. and pressure of about two atmospheres.

Pharmaceutically acceptable acid addition salts of the compounds offormula I are prepared by reacting a free base of formula I with anappropriate acid. Free bases of formula I are prepared by reacting anacid addition salt of a compound of formula I with an appropriate base.

The following specific description is given to enable those skilled inthe art to more clearly understand and practice the invention. It shouldnot be considered as a limitation upon the scope of the invention, butmerely as being illustrative and representative thereof.

PREPARATION 1 (Preparation of Compounds of Formula III Wherein A isBenzyloxy) (Step 1)

The carboxy function of 4-hydroxy-3-nitrophenylacetic acid (II) is firstprotected by forming the methyl ester using HCl in methanol, theprocedure for which is known in the art. Then, 10.5 g methyl4-hydroxy-3-nitrophenylacetate and 10 g benzyl chloride are reacted with5 g potassium carbonate in ethanol. The product is extracted with ether.

PREPARATION 2 (Preparation of Compounds of Formula IV Wherein A isHydrogen or Benzyloxy) (Step 2)

(A) 40 g of 3-nitrophenylacetic acid was added to a solution of 26 ml of10M borane-methyl sulfide in 200 ml of THF, and the mixture was stirredat 25° C. for 3 hr. The solution was then acidified with HCl inmethanol, followed by evaporation of the solvent. The product3-nitrophenylethanol (IV, A=H) was partitioned between diethyl ether(Et₂ O) and aqueous sodium carbonate, and the Et₂ O layer dried oversodium sulfate. Evaporation of the Et₂ O afforded 34.8 g of3-nitrophenylethanol (IV, A=H) as an oil.

(B) Similarly, proceeding as in Part A above, but substituting methyl4-benzyloxy-3-nitrophenylacetate for 3-nitrophenylacetic acid, thecompound 4-benzyloxy-3-nitrophenylethanol (IV, A=BzO) is produced.

PREPARATION 3 (Preparation of Compounds of Formula V) (Step 3)

(A) 34.6 g of 3-nitrophenylethanol (IV, A=H) was added to 41 g ofp-toluenesulfonyl chloride in 200 ml of pyridine at 0° C. and allowed tostand for 24 hr. Water was added, and the mixture extracted with ethylacetate. The ethyl acetate extract was washed with 5% HCl, water, andbrine, dried over Na₂ SO₄, and evaporated to a residue. The residue wasrecrystallized from Et₂ O to afford 34 g of 3-nitrophenylethyltosylate(V, A=H).

(B) Similarly, proceeding as in Part A above, but substituting4-benzyloxy-3-nitrophenylethanol for 3-nitrophenylethanol, the compound4-benzyloxy-3-nitrophenylethyltosylate (V, A=BzO) is produced.

PREPARATION 4 (Preparation of HNR₁ R₂)

(A) 25.3 g of phenethanol (available commercially from, e.g., AldrichChemical Co.) is added to 41 g of p-toluenesulfonyl chloride in 200 mlof pyridine at 0° C. and allowed to stand for 24 h. Water is added, andthe mixture extracted with ethyl acetate. The ethyl acetate extract waswashed with 5% HCl, water, and brine, dried over Na₂ SO₄, and evaporatedto a residue. The resulting tosyloxyethylbenzene is then stirred with12.2 g of n-propylamine in 100 ml of DMF at 65° C. for one hour. Thesolution is diluted with water and acidified with HCl. The mixture isthen washed with Et₂ O, basified with NH₄ OH, and extracted with ethylacetate. Evaporation of the solvent (after drying over Na₂ SO₄) producesN-propyl-N-phenethylamine (HNR₁ R₂).

(B) Similarly, proceeding as in Part A above, but substitutingethylamine and butylamine for propylamine, the following compounds areproduced:

N-ethyl-N-phenethylamine;

N-butyl-N-phenethylamine.

(C) Similarly, proceeding as in Parts A and B above, but substituting4-benzyloxyphenethanol, 3-nitrophenethanol, 4-phenylbutanol,3-nitro-1-hydroxymethylbenzene, 4-methylphenethanol, 4-butylphenethanol,3-methoxyphenethanol, and 4-butoxyphenethanol for phenethanol, thefollowing compounds are produced:

N-propyl-N-(4-benzyloxyphenethyl)amine;

N-butyl-N-(4-benzyloxyphenethyl)amine;

N-ethyl-N-(3-nitrophenyl)ethylamine;

N-propyl-N-phenylbutylamine;

N-ethyl-N-(3-nitrophenyl)methylamine;

N-butyl-N-(4-methylphenyl)ethylamine;

N-propyl-N-(4-butylphenethyl)amine;

N-propyl-N-(3-methoxyphenethyl)amine; and

N-propyl-N-(3-butoxyphenethyl)amine.

PREPARATION 5 (Preparation of Compounds of Formula VI) (Step 4)

(A) A mixture of 18.8 g of 3-nitrophenylethyl-2-tosylate and 25 ml ofN-propyl-N-phenethylamine in 100 ml of DMF was stirred at 65° C. for 12hr. The solution was diluted with water and acidified with HCl. Themixture was then washed with Et₂ O, basified with NH₄ OH, and extractedwith ethyl acetate. Evaporation of the solvent (after drying over Na₂SO₄) produced 10.1 g of 3-(2-N-propyl-N-phenethylaminoethyl)nitrobenzene(VI, A=H).

(B) Similarly, proceeding as above, substituting the compounds preparedin Preparation 4 (B-C) for N-propyl-N-phenethylamine, the followingcompounds (VI, A=H) are prepared:

3-(2-N-ethyl-N-phenethylaminoethyl)nitrobenzene;

3-(2-N-butyl-N-benzylaminoethyl)nitrobenzene;

3-[2-N-propyl-N-(4-benzyloxyphenethyl)aminoethyl]nitrobenzene;

3-[2-N-butyl-N-(4-benzyloxyphenethyl)aminoethyl]nitrobenzene;

3-[2-N-ethyl-N-(3-nitrophenyl)ethylaminoethyl]nitrobenzene;

3-(2-N-propyl-N-phenylbutylaminoethyl)nitrobenzene;

3-[2-N-ethyl-N-(3-nitrophenyl)methylaminoethyl]nitrobenzene;

3-[2-N-butyl-N-(4-methylphenyl)ethylaminoethyl]nitrobenzene;

3-[2-N-propyl-N-(4-aminophenethyl)aminoethyl]nitrobenzene;

3-[2-N-propyl-N-(4-butylphenyl)methylaminoethyl]nitrobenzene;

3-[2-N-propyl-N-(3-methoxyphenyl)ethylaminoethyl]nitrobenzene; and

3-[2-N-propyl-N-(4-butoxyphenethyl)aminoethyl]nitrobenzene.

(C) Similarly, proceeding as in Part A and Part B above, butsubstituting 4-benzyloxy-3-nitrophenylethyltosylate for3-nitrophenylethyltosylate, the following compounds (VI, A=BzO) areproduced:

2-benzyloxy-5-(2-N-propyl-N-phenethylaminoethyl)nitrobenzene

2-benzyloxy-5-(2-N-ethyl-N-phenethylaminoethyl)nitrobenzene;

2-benzyloxy-5-[2-N-propyl-N-(4-benzyloxyphenethyl)aminoethyl]nitrobenzene;

2-benzyloxy-5-[2-N-butyl-N-(4-benzyloxyphenethyl)aminoethyl]nitrobenzene;

2-benzyloxy-5-[2-N-ethyl-N-(3-nitrophenyl)ethylaminoethyl]nitrobenzene;

2-benzyloxy-5-(2-N-propyl-N-phenylbutylaminoethyl)nitrobenzene;

2-benzyloxy-5-[2-N-ethyl-N-(3-nitrophenyl)methylaminoethyl]nitrobenzene;

2-benzyloxy-5-[2-N-butyl-N-(4-methylphenyl)ethylaminoethyl]nitrobenzene;

2-benzyloxy-5-[2-N-propyl-N-(4-aminophenethyl)aminoethyl]nitrobenzene;

2-benzyloxy-5-[2-N-propyl-N-(4-butylphenylethyl)aminoethyl]nitrobenzene;

2-benzyloxy-5-[2-N-propyl-N-(3-methoxyphenylethyl)aminoethyl]nitrobenzene;and

2-benzyloxy-5-[2-N-propyl-N-(4-butoxyphenethyl)aminoethyl]nitrobenzene.

PREPARATION 6 (Preparation of Compounds of Formula VII, NovelIntermediates of the Invention) (Step 5)

(A) To 10.1 g of 3-(2-N-propyl-N-phenethylaminoethyl)nitrobenzene (VI)in 200 ml of ethanol was added 1.0 g of Raney nickel and the solutionheated to reflux. A solution of 10 ml of hydrazine hydrate in ethanolwas slowly added. After filtration and evaporation, the mixture yielded6.8 g of 3-(2-N-propyl-N-phenethylaminoethyl)aniline (VII, A=H) as anoil.

(B) Similarly, proceeding as in Part A above, but substituting thecompounds made in Preparation 5(B) above for3-(2-N-propyl-N-phenethylaminoethyl)nitrobenzene, the followingcompounds are prepared:

3-(2-N-ethyl-N-phenethylaminoethyl)aniline;

3-(2-N-butyl-N-benzylaminoethyl)aniline;

3-[2-N-propyl-N-(4-benzyloxyphenethyl)aminoethyl]aniline;

3-[2-N-butyl-N-(4-benzyloxyphenethyl)aminoethyl]aniline;

3-[2-N-ethyl-N-(3-aminophenyl)ethylaminoethyl]aniline;

3-(2-N-propyl-N-phenylbutylaminoethyl)aniline;

3-[2-N-ethyl-N-(3-aminophenyl)methylaminoethyl]aniline;

3-[2-N-butyl-N-(4-methylphenyl)ethylaminoethyl]aniline;

3-[2-N-propyl-N-(4-aminophenethyl)aminoethyl]aniline;

3-[2-N-propyl-N-(4-butylphenyl)methylaminoethyl]aniline;

3-[2-N-propyl-N-(3-methoxyphenyl)ethylaminoethyl]aniline; and

3-[2-N-propyl-N-(4-butoxyphenethyl)aminoethyl]aniline.

(C) Similarly, proceeding as in Part A and Part B above, butsubstituting the compounds prepared in Preparation 5(C) above for3-(2-N-propyl-N-phenethylaminoethyl)nitrobenzene, the followingcompounds (VII, A=BzO) are prepared:

2-benzyloxy-5-(2-N-propyl-N-phenethylaminoethyl)aniline;

2-benzyloxy-5-(2-N-ethyl-N-phenethylaminoethyl)aniline;

2-benzyloxy-5-[2-N-propyl-N-(4-benzyloxyphenethyl)aminoethyl]aniline;

2-benzyloxy-5-[2-N-butyl-N-(4-benzyloxyphenethyl)aminoethyl]aniline;

2-benzyloxy-5-[2-N-ethyl-N-(3-aminophenyl)ethylaminoethyl]aniline;

2-benzyloxy-5-(2-N-propyl-N-phenylbutylaminoethyl)aniline;

2-benzyloxy-5-[2-N-ethyl-N-(3-aminophenyl)methylaminoethyl]aniline;

2-benzyloxy-5-[2-N-butyl-N-(4-methylphenyl)ethylaminoethyl]aniline;

2-benzyloxy-5-[2-N-propyl-N-(4-aminophenethyl)aminoethyl]aniline;

2-benzyloxy-5-[2-N-propyl-N-(4-butylphenyl)methylaminoethyl]aniline;

2-benzyloxy-5-[2-N-propyl-N-(3-methoxyphenyl)ethylaminoethyl]aniline;and

2-benzyloxy-5-[2-N-propyl-N-(4-butoxyphenethyl)aminoethyl]aniline.

EXAMPLE 1 (Preparation of Compounds of Formula VIIIa) (Step 6a)

(A) 3.4 g of sodium formate is added to 3.6 ml of acetyl chloride in 20ml of THF at 0° C. and allowed to stand for 24 hr to form formic aceticanhydride. To this solution is added 10 g of3-(2-N-propyl-N-phenethylaminoethyl)aniline in 50 ml of pyridine. Thesolution is allowed to stand at 0° C. for 12 hr, and is then added towater and extracted with CH₂ Cl₂. The solvent is evaporated, and theresidue is purified by silica gel chromatography to afford3-(2-N-propyl-N-phenethylaminoethyl)formanilide (VIIIa, A=H).

(B) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Preparation 6(B) above for3-(2-N-propyl-N-phenethylaminoethyl)aniline, the following compounds(VIIIa, A=H) are prepared:

3-(2-N-ethyl-N-phenethylaminoethyl)formanilide;

3-(2-N-butyl-N-benzylaminoethyl)formanilide;

3-[2-N-propyl-N-(4-benzyloxyphenethyl)aminoethyl]formanilide;

3-[2-N-butyl-N-(4-benzyloxyphenethyl)aminoethyl]formanilide;

3-[2-N-ethyl-N-(3-aminophenethyl)aminoethyl]formanilide;

3-(2-N-propyl-N-phenylbutylaminoethyl)formanilide;

3-[2-N-ethyl-N-(3-aminophenyl)methylaminoethyl]formanilide;

3-[2-N-butyl-N-(4-methylphenyl)ethylaminoethyl]formanilide;

3-[2-N-propyl-N-(4-aminophenethyl)aminoethyl]formanilide;

3-[2-N-propyl-N-(4-butylphenethyl)aminoethyl]formanilide;

3-[2-N-propyl-N-(3-methoxyphenethyl)aminoethyl]formanilide; and

3-[2-N-propyl-N-(4-butoxyphenethyl)aminoethyl]formanilide.

(C) Similarly, proceeding as in Part A and Part B above, butsubstituting the compounds prepared in Preparation 6(C) for3-(2-N-propyl-N-phenethylaminoethyl)aniline, the following compounds(VIIIa, A=BzO) are prepared:

2-benzyloxy-5-(2-N-propyl-N-phenethylaminoethyl)formanilide;

2-benzyloxy-5-(2-N-ethyl-N-phenethylaminoethyl)formanilide;

2-benzyloxy-5-[2-N-propyl-N-(4-benzyloxyphenethyl)aminoethyl]formanilide;

2-benzyloxy-5-[2-N-butyl-N-(4-benzyloxyphenethyl)aminoethyl]formanilide;

2-benzyloxy-5-[2-N-ethyl-N-(3-aminophenethyl)aminoethyl]formanilide;

2-benzyloxy-5-(2-N-propyl-N-phenylbutylaminoethyl)formanilide;

2-benzyloxy-5-[2-N-ethyl-N-(3-aminophenyl)methylaminoethyl]formanilide;

2-benzyloxy-5-[2-N-butyl-N-(4-methylphenethyl)aminoethyl]formanilide;

2-benzyloxy-5-[2-N-propyl-N-(4-aminophenethyl)aminoethyl]formanilide;

2-benzyloxy-5-[2-N-propyl-N-(4-butylphenethyl)aminoethyl]formanilide;

2-benzyloxy-5-[2-N-propyl-N-(3-methoxyphenethyl)aminoethyl]formanilide;and

2-benzyloxy-5-[2-N-propyl-N-(4-butoxyphenethyl)aminoethyl]formanilide.

EXAMPLE 2 (Preparation of Compounds of Formula VIIIb) (Step 6b)

(A) 3.5 g of 3-(2-N-propyl-N-phenethylaminoethyl)aniline in 20 ml ofpyridine is treated with 1 ml of acetyl chloride at 0° C. The solutionis added to water and extracted with CH₂ Cl₂. The solvent is evaporatedand the product 3-(2-N-propyl-N-phenethylaminoethyl)acetanilide (VIIIb,A=H) is purified by silica gel chromatography (HBr salt m.p. 212°-213°C.).

(B) Similarly, proceeding as in Part A above, but substituting propanoylchloride or butanoyl chloride for acetyl chloride, the followingcompounds are prepared:

3-(2-N-propyl-N-phenethylaminoethyl)propionanilide;

3-(2-N-propyl-N-phenethylaminoethyl)butyranilide.

(C) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Preparation 6(B) above for3-(2-N-propyl-N-phenethylaminoethyl)aniline, the following compounds(VIIIb, A=H) are prepared:

3-(2-N-ethyl-N-phenethylaminoethyl)acetanilide;

3-(2-N-butyl-N-benzylaminoethyl)acetanilide;

3-[2-N-propyl-N-(4-benzyloxyphenethyl)aminoethyl]acetanilide;

3-[2-N-butyl-N-(4-benzyloxyphenethyl)aminoethyl]acetanilide;

3-[2-N-ethyl-N-(3-aminophenethyl)aminoethyl]acetanilide;

3-(2-N-propyl-N-phenylbutylaminoethyl)acetanilide;

3-[2-N-ethyl-N-(3-aminophenyl)methylaminoethyl]acetanilide;

3-[2-N-butyl-N-(4-methylphenyl)ethylaminoethyl]acetanilide;

3-[2-N-propyl-N-(4-aminophenethyl)aminoethyl]acetanilide;

3-[2-N-propyl-N-(4-butylphenylethyl)aminoethyl]acetanilide;

3-[2-N-propyl-N-(3-methoxyphenylethyl)aminoethyl]acetanilide; and

3-[2-N-propyl-N-(4-butoxyphenethyl)aminoethyl]acetanilide.

(D) Similarly, proceeding as in Parts A, B, and C above, butsubstituting the compounds made in Preparation 6(C) for3-(2-N-propyl-N-phenethylaminoethyl)aniline and propanoyl chloride orbutanoyl chloride for acetyl chloride, the corresponding propionanilideand butyranilide derivatives (VIIIb, A=H) are prepared.

(E) Similarly, proceeding as in Part A above, but substituting thecompounds made in Preparation 6(C) for3-(2-N-propyl-N-phenethylaminoethyl)aniline, the following compounds(VIIIb, A=BzO) are prepared:

2-benzyloxy-5-(2-N-propyl-N-phenethylaminoethyl)acetanilide;

2-benzyloxy-5-(2-N-ethyl-N-phenethylaminoethyl)acetanilide;

2-benzyloxy-5-[2-N-propyl-N-(4-benzyloxyphenethyl)aminoethyl]acetanilide;

2-benzyloxy-5-[2-N-butyl-N-(4-benzyloxyphenethyl)aminoethyl]acetanilide;

2-benzyloxy-5-[2-N-ethyl-N-(3-aminophenethyl)aminoethyl]acetanilide;

2-benzyloxy-5-(2-N-propyl-N-phenylbutylaminoethyl)acetanilide;

2-benzyloxy-5-[2-N-ethyl-N-(3-aminophenyl)methylaminoethyl]acetanilide;

2-benzyloxy-5-[2-N-butyl-N-(4-methylphenyl)ethylaminoethyl]acetanilide;

2-benzyloxy-5-[2-N-propyl-N-(4-aminophenethyl)aminoethyl]acetanilide;

2-benzyloxy-5-[2-N-propyl-N-(4-butylphenethyl)aminoethyl]acetanilide;

2-benzyloxy-5-[2-N-propyl-N-(3-methoxyphenylethyl)aminoethyl]acetanilide;and

2-benzyloxy-5-[2-N-propyl-N-(4-butoxyphenethyl)aminoethyl]acetanilide.

(F) Similarly, proceeding as in Parts B and E above, the corresponding2-benzyloxy-propionanilide and butyranilide derivatives (VIIIb, A=BzO)are prepared.

EXAMPLE 3 (Preparation of Compounds of Formula VIIIc) (Step 6c)

(A) A solution of 2.2 g of 3-(2-N-propyl-N-phenethylaminoethyl)anilinein 10 ml 2:1 water/acetic acid was treated with 1.5 g of potassiumcyanate in 5 ml of water. The mixture was then made basic with NH₄ OHand extracted with CH₂ Cl₂. The CH₂ Cl₂ was evaporated, and the residuedissolved in methanol. Then, 48% aqueous HBr or HCl was added until thesolution was acidic. The product,3-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene.HBr, (VIIIc, A=H) wasprecipitated from the solution with Et₂ O.

(B) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Preparation 6(B) above for3-(2-N-propyl-N-phenethylaminoethyl)aniline, the following compounds(VIIIc, A=H) are prepared:

3-(2-N-ethyl-N-phenethylaminoethyl)ureidobenzene.HBr;

3-(2-N-butyl-N-benzylaminoethyl)ureidobenzene.HBr;

3-[2-N-propyl-N-(4-benzyloxyphenethyl)aminoethyl]ureidobenzene.HBr;

3-[2-N-butyl-N-(4-benzyloxyphenethyl)aminoethyl]ureidobenzene.HBr;

3-[2-N-ethyl-N-(3-ureidophenyl)ethylaminoethyl]ureidobenzene.HBr;

3-(2-N-propyl-N-phenylbutylaminoethyl)ureidobenzene.HBr;

3-[2-N-ethyl-N-(3-ureidophenyl)methylaminoethyl]ureidobenzene.HBr;

3-[2-N-butyl-N-(4-methylphenyl)ethylaminoethyl]ureidobenzene.HBr;

3-[2-N-propyl-N-(4-ureidophenethyl)aminoethyl]ureidobenzene.HBr;

3-[2-N-propyl-N-(4-butylphenylethyl)aminoethyl]ureidobenzene.HBr;

3-[2-N-propyl-N-(3-methoxyphenylethyl)aminoethyl]ureidobenzene.HBr; and

3-[2-N-propyl-N-(4-butoxyphenethyl)aminoethyl]ureidobenzene.HBr.

(C) Similarly, proceeding as in Part A and Part B above, butsubstituting the compounds prepared in Preparation 6(C) for3-(2-N-propyl-N-phenethylaminoethyl)aniline, the following compounds(VIIIc, A=BzO) are produced:

2-benzyloxy-5-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene.HBr;

2-benzyloxy-5-(2-N-ethyl-N-phenethylaminoethyl)ureidobenzene.HBr;

2-benzyloxy-5-[2-N-propyl-N-(4-benzyloxyphenethyl)aminoethyl]ureidobenzene.HBr;

2-benzyloxy-5-[2-N-butyl-N-(4-benzyloxyphenethyl)aminoethyl]ureidobenzene.HBr;

2-benzyloxy-5-[2-N-ethyl-N-(3-ureidophenyl)ethylaminoethyl]ureidobenzene.HBr;

2-benzyloxy-5-(2-N-propyl-N-phenylbutylaminoethyl)ureidobenzene.HBr;

2-benzyloxy-5-[2-N-ethyl-N-(3-ureidophenyl)methylaminoethyl]ureidobenzene.HBr;

2-benzyloxy-5-[2-N-butyl-N-(4-methylphenyl)ethylaminoethyl]ureidobenzene.HBr;

2-benzyloxy-5-[2-N-propyl-N-(4-ureidophenethyl)aminoethyl]ureidobenzene.HBr;

2-benzyloxy-5-[2-N-propyl-N-(4-butylphenethyl)aminoethyl]ureidobenzene.HBr;

2-benzyloxy-5-[2-N-propyl-N-(3-methoxyphenylethyl)aminoethyl]ureidobenzene.HBr;and

2-benzyloxy-5-[2-N-propyl-N-(4-butoxyphenethyl)aminoethyl]ureidobenzene.HBr.

EXAMPLE 4 (Preparation of Compounds of Formula VIIId) (Step 6d)

(A) A solution of 2.2 g of 3-(2-N-propyl-N-phenethylaminoethyl)anilinein 10 ml of 2:1 water/acetic acid is treated with 1.1 g of methylisocyanate in 5 ml of water. The mixture is made basic with NH₄ OH andextracted with CH₂ Cl₂. The solvent is evaporated to afford1-[3-(2-N-propyl-N-phenethylaminoethyl)phenyl]-3-methylurea (VIIId,A=H).

(B) Similarly, proceeding as in Part A above, but substitutingethylisocyanate or propylisocyanate for methyl isocyanate, the followingcompounds (VIIId, A=H) are prepared:

1-[3-(2-N-propyl-N-phenethylaminoethyl)phenyl]-3-ethylurea;

1-[3-(2-N-propyl-N-phenethylaminoethyl)phenyl]-3-propylurea.

(C) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Preparation 6(B) above for3-(2-N-propyl-N-phenethylaminoethyl)aniline, the following compounds(VIIId, A=H) are prepared:

1-[3-(2-N-ethyl-N-phenethylaminoethyl)phenyl]-3-methylurea;

1-[3-(2-N-butyl-N-benzylaminoethyl)phenyl]-3-methylurea;

1-(3-[2-N-propyl-N-(4-benzyloxyphenethyl)aminoethyl]phenyl]-3-methylurea;

1-(3-[2-N-butyl-N-(4-benzyloxyphenethyl)aminoethyl]phenyl]-3-methylurea;

1-(3-[2-N-ethyl-N-(3-methylureidophenyl)ethylaminoethyl]phenyl]-3-methylurea;

1-[3-(2-N-propyl-N-phenylbutylaminoethyl)phenyl]-3-methylurea;

1-(3-[2-N-ethyl-N-(3-methylureidophenyl)methylaminoethyl]phenyl)-3-methylurea;

1-(3-[2-N-butyl-N-(4-methylphenyl)ethylaminoethyl]phenyl)-3-methylurea;

1-(3-[2-N-propyl-N-(4-methylureidophenethyl)aminoethyl]phenyl)-3-methylurea;

1-(3-[2-N-propyl-N-(4-butylphenylethyl)aminoethyl]phenyl)-3-methylurea;

1-(3-[2-N-propyl-N-(3-methoxyphenylethyl)aminoethyl]phenyl)-3-methylurea;and

1-(3-[2-N-propyl-N-(4-butoxyphenethyl)aminoethyl]phenyl)-3-methylurea.

(D) Similarly, proceeding as in Part A above, but substituting thecompounds made in Preparation 6(C) for3-(2-N-propyl-N-phenethylaminoethyl)aniline, the following compounds(VIIId, A=BzO) are prepared:

1-[2-benzyloxy-5-(2-N-propyl-N-phenethylaminoethyl)phenyl]-3-methylurea;

1-[2-benzyloxy-5-(2-N-ethyl-N-phenethylaminoethyl)phenyl]-3-methylurea;

1-(2-benzyloxy-5-[2-N-propyl-N-(4-benzyloxyphenethyl)aminoethyl]phenyl)-3-methylurea;

1-(2-benzyloxy-5-[2-N-butyl-N-(4-benzyloxyphenethyl)aminoethyl]phenyl)-3-methylurea;

1-(2-benzyloxy-5-[2-N-ethyl-N-(3-methylureidophenyl)ethylaminoethyl]phenyl)-3-methylurea;

1-[2-benzyloxy-5-(2-N-propyl-N-phenylbutylaminoethyl)phenyl]-3-methylurea;

1-(2-benzyloxy-5-[2-N-ethyl-N-(3-methylureidophenyl)methylaminoethyl]phenyl)-3-methylurea;

1-(2-benzyloxy-5-[2-N-butyl-N-(4-methylphenyl)ethylaminoethyl]phenyl)-3-methylurea;

1-(2-benzyloxy-5-[2-N-propyl-N-(4-methylureidophenethyl)aminoethyl]phenyl)-3-methylurea;

1-(2-benzyloxy-5-[2-N-propyl-N-(4-butylphenethyl)aminoethyl]phenyl)-3-methylurea;

1-(2-benzyloxy-5-[2-N-propyl-N-(3-methoxyphenylethyl)aminoethyl]phenyl)-3-methylurea;and

1-(2-benzyloxy-5-[2-N-propyl-N-(4-butoxyphenethyl)aminoethyl]phenyl)-3-methylurea.

(E) Similarly, proceeding as in Part B above, but substituting thecompounds made in Preparation 6(C) for3-(2-N-propyl-N-phenethylaminoethyl)aniline, the corresponding3-ethylurea and 3-propylurea compounds (VIIId, A=BzO) are prepared.

EXAMPLE 5 (Preparation of Compounds of Formula I wherein R₃ isHydroxy)(Step 7)

(A) A solution of 3.3 g of2-benzyloxy-5-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene.HBr(VIIIc, A=BzO) in 150 ml of methanol was hydrogenated with 0.5 g of 10%Pd-C for 6 hr. at 2 atmospheres and 60° C. Filtration and evaporationafforded an oil which was dissolved in methanol and acidified withhydrogen bromide. Addition of Et₂ O precipitated the HBr salt,2-hydroxy-5-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene.HBr (I.HBr).

Similarly, proceeding as above but substituting hydrogen chloride forhydrogen bromide, the hydrochloride salts are prepared.

(B) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Example 1(C) for2-benzyloxy-5-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene.HBr, thefollowing compounds are prepared:

2-hydroxy-5-(2-N-propyl-N-phenethylaminoethyl)formanilide;

2-hydroxy-5-(2-N-ethyl-N-phenethylaminoethyl)formanilide;

2-hydroxy-5-[2-N-propyl-N-(4-hydroxyphenethyl)aminoethyl]formanilide;

2-hydroxy-5-[2-N-butyl-N-(4-hydroxyphenethyl)aminoethyl]formanilide;

2-hydroxy-5-[2-N-ethyl-N-(3-aminophenyl)ethylaminoethyl]formanilide;

2-hydroxy-5-(2-N-propyl-N-phenylbutylaminoethyl)formanilide;

2-hydroxy-5-[2-N-ethyl-N-(3-aminophenyl)methylaminoethyl]formanilide;

2-hydroxy-5-[2-N-butyl-N-(4-methylphenyl)ethylaminoethyl]formanilide;

2-hydroxy-5-[2-N-propyl-N-(4-aminophenethyl)aminoethyl]formanilide;

2-hydroxy-5-[2-N-propyl-N-(4-butylphenyl)aminoethyl]formanilide;

2-hydroxy-5-[2-N-propyl-N-(3-methoxyphenylethyl)aminoethyl]formanilide;and

2-hydroxy-5-[2-N-propyl-N-(4-butoxyphenethyl)aminoethyl]formanilide.

(C) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Example 2(E) for2-benzyloxy-5-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene.HBr, thefollowing compounds are produced:

2-hydroxy-5-(2-N-propyl-N-phenethylaminoethyl)acetanilide;

2-hydroxy-5-(2-N-ethyl-N-phenethylaminoethyl)acetanilide;

2-hydroxy-5-[2-N-propyl-N-(4-hydroxyphenethyl)aminoethyl]acetanilide;

2-hydroxy-5-[2-N-butyl-N-(4-hydroxyphenethyl)aminoethyl]acetanilide;

2-hydroxy-5-[2-N-ethyl-N-(3-aminophenyl)ethylaminoethyl]acetanilide;

2-hydroxy-5-(2-N-propyl-N-phenylbutylaminoethyl)acetanilide;

2-hydroxy-5-[2-N-ethyl-N-(3-aminophenyl)methylaminoethyl]acetanilide;

2-hydroxy-5-[2-N-butyl-N-(4-methylphenyl)ethylaminoethyl]acetanilide;

2-hydroxy-5-[2-N-propyl-N-(4-aminophenethyl)aminoethyl]acetanilide;

2-hydroxy-5-[2-N-propyl-N-(4-butylphenethyl)aminoethyl]acetanilide;

2-hydroxy-5-[2-N-propyl-N-(3-methoxyphenylethyl)aminoethyl]acetanilide;and

2-hydroxy-5-[2-N-propyl-N-(4-butoxyphenethyl)aminoethyl]acetanilide.

(D) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Example 2(F) for2-benzyloxy-5-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene.HBr, thecorresponding propionanilide and butyranilide derivatives (VIIIb, A=H)are prepared.

(E) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Example 3(C) for2-benzyloxy-5-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene.HBr, thefollowing compounds are prepared:

2-hydroxy-5-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene.HBr;

2-hydroxy-5-(2-N-ethyl-N-phenethylaminoethyl)ureidobenzene.HBr;

2-hydroxy-5-[2-N-propyl-N-(4-hydroxyphenethyl)aminoethyl]ureidobenzene.HBr;

2-hydroxy-5-[2-N-butyl-N-(4-hydroxyphenethyl)aminoethyl]ureidobenzene.HBr;

2-hydroxy-5-[2-N-ethyl-N-(3-aminophenyl)ethylaminoethyl]ureidobenzene.HBr;

2-hydroxy-5-(2-N-propyl-N-phenylbutylaminoethyl)ureidobenzene.HBr;

2-hydroxy-5-[2-N-ethyl-N-(3-aminophenyl)methylaminoethyl]ureidobenzene.HBr;

2-hydroxy-5-[2-N-butyl-N-(4-methylphenyl)ethylaminoethyl]ureidobenzene.HBr;

2-hydroxy-5-[2-N-propyl-N-(4-aminophenethyl)aminoethyl]ureidobenzene.HBr;

2-hydroxy-5-[2-N-propyl-N-(4-butylphenethyl)aminoethyl]ureidobenzene.HBr;

2-hydroxy-5-[2-N-propyl-N-(3-methoxyphenylethyl)aminoethyl]ureidobenzene.HBr;and

2-hydroxy-5-[2-N-propyl-N-(4-butoxyphenethyl)aminoethyl]ureidobenzene.HBr.

(F) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Example 4(D) for2-benzyloxy-5-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene.HBr, thefollowing compounds are prepared:

1-[2-hydroxy-5-(2-N-propyl-N-phenethylaminoethyl)phenyl]-3-methylurea;

1-[2-hydroxy-5-(2-N-ethyl-N-phenethylaminoethyl)phenyl]-3-methylurea;

1-(2-hydroxy-5-[2-N-propyl-N-(4-hydroxyphenethyl)aminoethyl]phenyl)-3-methylurea;

1-(2-hydroxy-5-[2-N-butyl-N-(4-hydroxyphenethyl)aminoethyl]phenyl)-3-methylurea;

1-(2-hydroxy-5-[2-N-ethyl-N-(3-aminophenyl)ethylaminoethyl]phenyl)-3-methylurea;

1-[2-hydroxy-5-(2-N-propyl-N-phenylbutylaminoethyl)phenyl]-3-methylurea;

1-(2-hydroxy-5-[2-N-ethyl-N-(3-aminophenyl)methylaminoethyl]phenyl)-3-methylurea;

1-(2-hydroxy-5-[2-N-butyl-N-(4-methylphenyl)ethylaminoethyl]phenyl)-3-methylurea;

1-(2-hydroxy-5-[2-N-propyl-N-(4-aminophenethyl)aminoethyl]phenyl)-3-methylurea;

1-(2-hydroxy-5-[2-N-propyl-N-(4-butylphenethyl)aminoethyl]phenyl)-3-methylurea;

1-(2-hydroxy-5-[2-N-propyl-N-(3-methoxyphenylethyl)aminoethyl]phenyl)-3-methylurea;and

1-(2-hydroxy-5-[2-N-propyl-N-(4-butoxyphenethyl)aminoethyl]phenyl)-3-methylurea.

(G) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Example 4(E) for2-benzyloxy-5-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene.HBr, thecorresponding 3-ethylurea and 3-propylurea derivatives are prepared.

EXAMPLE 6 (Preparation of Salts From Free Bases)

8.0 g of 3-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene is dissolvedin methanol and acidified with methanolic HCl. The precipitate is washedwith Et₂ O to give 7.0 g of the hydrochloride salt of3-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene.

In a similar manner, all compounds of formula I in base form prepared inaccordance with the methods described above can be converted to theirpharmaceutically acceptable acid addition salts by treatment with theappropriate acid, for example, HBr, sulfuric acid, nitric acid,phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvicacid, malonic acid, succinic acid, malic acid, maleic acid, fumaricacid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acidand the like.

EXAMPLE 7 (Preparation of Free Bases From Salts)

A solution of 3.5 g of3-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene.HCl in water (50 ml)is adjusted to pH 12 with NH₄ OH solution and extracted with methylenechloride. The methylene chloride is then evaporated to afford 3 g of3-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene as the free base.

In a similar manner, all acid addition salts of compounds of formula Iprepared in accordance with the methods described above can be convertedto their free base form.

EXAMPLE 8 (Formulations)

The following example illustrates the preparation of representativepharmaceutical formulations containing an active compound of Formula I,e.g., 3-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene.

    ______________________________________                                        Intraocular Solution                                                          ______________________________________                                        Active compound        0.10    g                                              Benzalkonium Chloride  0.01    g                                              EDTA                   0.10    g                                              Sodium Phosphate Buffer qs                                                                           pH 7.4                                                 2% Boric acid solution qs                                                                            100     ml                                             ______________________________________                                    

The active compound is dissolved in 2% Boric acid solution, benzalkoniumchloride, sodium phosphate buffer and ethylenediaminetetraacetic acid(EDTA). The solution is then filtered through a 0.2 micron membranefilter and packaged under sterile conditions.

    ______________________________________                                        Intraocular Ointment                                                          ______________________________________                                        Active Compound        1      g                                               Benzalkonium Chloride  0.1    g                                               EDTA                   1.0    g                                               White Wax              50     g                                               Petrolatum             950    g                                               ______________________________________                                    

The wax is melted over a water bath. The petrolatum is then added andheated until it liquifies. The mixture is then cooled and stirred untilit congeals. The remaining ingredients are then added as micronizedpowders and the mixture packaged under sterile conditions.

EXAMPLE 9 (Ocular Irritation Test)

Each studied compound is tested individually on a single animal byadministering, at the same time, into one eye of the animal theophthalmic solution with the test compound as an active ingredient andto the other eye only vehicle ophthalmic solution. An irritation, ifany, caused by tested compounds is compared to the non-irritating effectof the vehicle ophthalmic solution applied to the other eye. Irritationis measured by the number of blinks of each eye during the same timeperiod. Tests are performed on rats, dogs and monkeys.

Ophthalmic solutions with compounds of the invention as the activeingredient are prepared at the concentrations of 0.01% to 0.5%. One dropof the test ophthalmic solution with active ingredient is administereddirectly into the conjuctival sack of the rat's left eye. At the sametime one drop of vehicle is administered to the conjunctival sack of therat's right eye.

Irritation of each eye is measured by counting the number of blinks forone minute after the application. The results are expressed as the meannumber of blinks ± standard error per eye. The mean number ofblinks/minute is averaged for the vehicle treatment and compared to thedrug treated eye. Each compound is tested similarly in mongrel dogs andrhesus monkeys.

The compounds of this invention do not elicit any irritation of the eyesin any of the three species at any concentration which is used fortesting (i.e., 0.12-0.5%) and their effects are comparable to the effectof the vehicle ophthalmic solution without any drug added.

EXAMPLE 10 (Reduction Of Intraocular Pressure)

This example illustrates the effect of compounds of the currentinvention on intraocular pressure (IOP).

Two groups of normal albino white New Zealand rabbits are used for thisstudy.

Control group: 4 animals

Experimental group: 8 animals

Experimental schedule

At time 0, the intraocular pressure of both eyes of each animal incontrol and experimental groups is determined.

All animals receive the treatment either with saline (control group) orthe tested compound (experimental group) immediately after the 0 hourintraocular pressure reading. The control group receives 50 μl ofvehicle in both eyes. Experimental animals receive 50 μl of vehicle inthe left eyes and 50 μl of 1% solution of tested compound in the righteyes.

Intraocular pressure is measured at 30 minutes, 1, 2, and 4 hours.

Experimental Procedure

The effects of tested drug on intraocular pressure of the rabbit isdetermined using a Digilab Model 30D pneuma-tonometer. Initial IOPreadings are obtained in all animals after the administration of 50 μlof 0.5% Opthaine (proparacaine hydrochloride). A group of 4 rabbitsserves as control and is treated with 50 μl of saline in both eyes.Eight additional rabbits receive 50 μl of test drug in the right eye,and 50 μl of drug vehicle is administered in the contralateral left eye.IOP readings are made 30 minutes, 1 hours, 2 hours, and 4 hours afterdrug administration. Rabbits are observed for any signs of ocularirritation.

This procedure permits the comparison of drug treated eye with thecontralateral vehicle treated eye, and also with saline treated eye. Forpurposes of statistical analysis comparisons are made between the drugtreated IOP values and vehicle treated contralateral eyes and also thesaline treated IOP values.

What is claimed is:
 1. A method for treating elevated intraocularpressure in a mammal, which method comprises administering directly tothe eye of a mammal in need of such treatment a therapeuticallyeffective amount of a compound of the formula I: ##STR5## or apharmaceutically acceptable acid addition salt thereof, wherein R₁ isalkyl of two to four carbon atoms;R₂ is --(CH₂)_(n) --C₆ H₄ --R₅ ;wheren is an integer from 1 to 4; and R₅ is --H, --OH, halo, loweralkyl, lower alkoxy, ureido, lower alkyl-ureido, lower alkyl-amido, orformamido; R₃ is hydro or hydroxy; and R₄ is hydro, lower alkyl, amino,or lower alkylamino.
 2. The method of claim 1 wherein n is
 2. 3. Themethod of claim 2 wherein R₃ is H.
 4. The method of claim 3 wherein R₄is --NH₂.
 5. The method of claim 4 wherein the compound is3-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene.
 6. The method ofclaim 4 wherein the compound is3-[2-N-propyl-N-(4-ureidophenethyl)aminoethyl]ureidobenzene.
 7. Themethod of claim 4 wherein the compound is3-[2-N-butyl-N-(4-hydroxyphenethyl)aminoethyl]ureidobenzene.
 8. Themethod of claim 2 wherein R₃ is OH.
 9. The method of claim 8 wherein R₄is --NH₂.
 10. The method of claim 9 wherein the compound is2-hydroxy-5-(2-N-propyl-N-phenethylaminoethyl)ureidobenzene.
 11. Themethod of claim 9 wherein the compound is2-hydroxy-5-[2-N-propyl-N-(4-hydroxyphenethyl)aminoethyl]ureidobenzene.12. The method of claim 1 wherein n is
 4. 13. The method of claim 12wherein R₃ is H.
 14. The method of claim 13 wherein R₄ is methyl. 15.The method of claim 14 wherein the compound is3-(2-N-propyl-N-phenylbutylaminoethyl)ureidobenzene.